TCF1 expression marks self-renewing human CD8+ T cells

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TCF1 expression marks self-renewing human CD8+ T cells by Radomir Kratchmarov, Arthur M. Magun, and Steven L. Reiner BloodAdv Volume 2(14):1685-1690 July 24, 2018 © 2018 by The American Society of Hematology

Radomir Kratchmarov et al. Blood Adv 2018;2:1685-1690 © 2018 by The American Society of Hematology

Memory CD8+T-cell heterogeneity associated with TCF1 expression. Memory CD8+T-cell heterogeneity associated with TCF1 expression. (A) Characterization of T-cell subsets in peripheral blood of healthy and chronically infected humans. CD4+/CD8+ T-cell ratios in donor subjects (top left). Identification of CD8+ T-cell subsets in peripheral blood: naive (CCR7+CD45RA+), TCM (CCR7+CD45RA−), TEM (CCR7−CD45RA−), and TEMRA (CCR7−CD45RA+) (bottom left). Distribution of naive and memory CD8+ T-cell subsets (top right). Subset frequencies were not significantly associated with infection status (2-way analysis of variance [ANOVA]). Steady-state expression (mean fluorescence intensity [MFI]) of TCF1 by CD8+ T cell subsets (bottom right). (B) Hierarchical expression of TCF1. Identification of TCF1-hi, TCF1-int, and TCF1-lo subsets within the bulk CD8+ T-cell compartment (left). Distribution of TCF1-subsets within traditional naive, TCM, TEM, and TEMRA populations (right). (C) Expression of transcription factors Eomes, LEF1, and T-bet by TCF1-hi, TCF1-int, and TCF1-lo populations in healthy donors. *P < .05. **P < .01. ***P < .001. Repeated measures 1-way ANOVA with Sidak correction. (D) Reciprocal expression of TCF1 and CD57 across CD8+ T-cell populations in healthy donors. Gate denotes frequency of the TCF1-lo CD57+ population. Results are representative of 5 independent donors. (E) Quiescent phenotype of TCF1-hi cells. Expression of CD127 (IL7-R), CD27 (costimulatory receptor), and CD57 (senescence marker) by TCF1 subsets in healthy donors. *P < .05; ***P < .001; n.s., not significant (repeated-measures 1-way ANOVA with Sidak correction). HCV, hepatitis C virus. Radomir Kratchmarov et al. Blood Adv 2018;2:1685-1690 © 2018 by The American Society of Hematology

Self-renewal of TCF1-hi CD8+T cells. Self-renewal of TCF1-hi CD8+T cells. Distinct functional properties of TCF1 subsets. (A) Peripheral blood mononuclear cells stimulated with 12-O-tetradecanoylphorbol 13-acetate/ionomycin and analyzed for cytokine (IFN-γ) and cytolytic molecule (granzyme B) expression and degranulation (CD107a). *P < .05; **P < .01 (repeated-measures 1-way ANOVA with Sidak correction). (B) TCF1-hi cells self-renew following T-cell receptor (TCR) stimulation. The histogram on the left shows steady-state TCF1 expression by FACS-sorted CCR7+CD45RA+CD57− (naive), CCR7+CD45RA−CD57− (TCM), CCR7−CD45RA−CD57− (TEM), and CCR7−CD57+ populations. Data are representative of 5 separate donors. FACS-sorted naive, TCM, TEM, and CCR7−CD57+CD8+ T cells were TCR stimulated (right). Cell division vs TCF1 expression at day 4 is shown. Gate denotes TCF1-hi population. Quantification of TCF1-hi population frequency (bottom left). *P < .05; ****P < .0001 (1-way ANOVA with the Sidak multiple comparisons test). (C) Earlier loss of TCF1-hi cells from TCM following activation. Naive and TCM populations were sorted and stimulated as in panel B. Frequency of TCF1-hi cells was quantified on day 4 for naive and TCM starting populations at each division number. *P < .05 (Student t test with Holm-Sidak correction for multiple comparisons). (D) Stepwise differentiation of TCF1-hi and TCF1-lo populations following activation of naive CD8+ T cells. Gating of undivided (P1), TCF1-hi (P2), and TCF1-lo (P3) populations at day 4 of culture following TCR stimulation of naive cells (top left). The remaining panels show representative histograms of CD27, CCR7, CD127, T-bet, and Eomes expression by each population. Activated CD57+ cells were included as a positive control for Eomes induction. Plots are representative of 3 independent donors. Radomir Kratchmarov et al. Blood Adv 2018;2:1685-1690 © 2018 by The American Society of Hematology